CA2197234A1 - Composition for the selective release of an active ingredient - Google Patents

Abstract

The present invention discloses a composition comprising, in that order, (a) a core of a material swelling in water; (b) a resilient, water insoluble, water permeable layer; (c) a layer containing one or more active ingredients; and (d) a layer of a material that becomes water permeable in a predetermined aqueous medium, capable of rupturing upon the expansion of the core. Also disclosed is the use of said composition as a drug.

Description

~ W096 ~ 93 Y ~ l / rl ./Y

2 1 9723 ~

ALLOWING COMPOSITION
A SELECTIVE RELEASE OF AN ACTIVE PRINCIPLE

The subject of the present invention is a composition allowing selective release of an active ingredient at level of a given site, and in particular a composition pharmaceutical allowing selective release of active ingredient in a target organ. The current invention relates more particularly to a composition pharmaceutical intended for oral administration, allowing selective release of the active ingredient at colon level.
Many pharmaceutical compositions have been ~ developed to allow release active ingredient. These compositions are for the most based on the principle of delayed release or prolonged release of the drug whether or not of a target organ.
EP-A-0 250 374 describes mini dosing units coated. The core of these is obtained by compression of a mixture of the active ingredient with polymers swelling in water by an osmosis mechanism, the polymer coating surrounding the core controlling the drug release.
EP-A-0 077 956 describes enteric microcapsules containing an active ingredient forming the nucleus which is surrounded a coating consisting essentially of ethylcellulose and an enteric polymeric material, a polymeric material swelling in water being ~ possibly incorporated in the core.
Gs-A-2 202 143 describes a pharmaceutical composition comprising a water-insoluble drug, dispersed in a matrix made up of microcrystalline cellulose and d ~ at least one cellulose derivative. such a composition w096 / 04893 2 1 9 7 2 3 ~ rl S IU / Y ~

leads to the prolonged release of the acti ~ principle on a period of at least 8 hours. these compositions can be coated with an enteric coating to allow release of m ~ iC - -t in the intestinal tract rather than in the stomach.
The dosage units described in these documents do not not allow immediate release from the active ingredient at the level of a specific organ; his speed of release is limited by its speed of diffusion through the matrix surrounding it or trapping it ~ ui can have for consequence that the entire administered dose is not released at the target organ. Indeed, in the case of the gastrointestinal tract, transit time varies from one individual to other in large measure, and the conditions prevailing in the gastrointestinal system ~, in particular the pH, also vary within wide limits.
Research carried out with the aim of obtaining a composition allowing selective release of active principles at the level of a target organ ~ ex. the colon) have so far focused either on the use of tablets, administered orally, coated with polymers that are broken down by bacteria present in the colon level, either on the use of tablets, orally administered, coated with a coating entertains.
In the first type of approach. we use the concept of prodrug or ~ pro-drug ", namely precursor of the principle active, according to which the active ingredient is linked to a polymer glucoside for example (Frlend, Phillips and ~ orzen, F.
Controlled Rel, 15, 47-54, (1991)). The main problem in this approach is that the drug itself is chemically modified and the release of the active ingredient is conditioned by bacterial hydrolysis in situ.
In the second type of approach, use is made of coatings made of polymers whose solubility depends on pH, and which dissolve at a pH higher than that of the stomach. Products can only dissolve when the pH value of the surrounding medium exceeds one certain value 2 ~ 97 ~ 3 ~

The use of tablets with this type of __ coating does not lead to satisfactory results and does not provide a targeted release of principles assets. Indeed, if we study the pH profile of the tract 5 gastrointestinal, we observe that the pH in the distal bowel varies between 6.8 and 7.2, then drops to a value of 4.5 to 6 at the bottom of the ~~
colon. Therefore, the pharmaceutical composition is designed so that the polymer coating dissolves at a 10 pH greater than or equal to 7; the polymer dissolves in m the intestine and the active ingredient is released at this level. Gold, the pH varies greatly from one individual to another. So if the pH remains at too low values, the coating enteri ~ ue will remain intact and the active ingredient will not be released. , -It is therefore clear that a control of the release of the active ingredient based only on the use of a coating degrading selectively to level or before reaching the target organ does not allow a targeted drug release at the drug level, <insert page 3a>
There is therefore a need for a composition allowing selective release of an active ingredient at level of a given site, and in particular for a pharmaceutical composition allowing a release selective of an active ingredient at the level of a target organ.
~ The object of the present invention is to eliminate disadvantages of existing pharmaceutical compositions, know a non-selective and prolonged release, and provide a co ~ position allowing selective release of an active ingredient at a given site, and in particular a pharmaceutical composition allowing a lib ~ ration selective active ingredient at a target organ, in especially the colon.
~ a subject of the present invention is a composition comprising, successively:
(a) a core (1) made of a swelling material in water;
(b) a layer (2) of an elastic material leaving pass the water and insoluble in water

3 MODIRE SHEET ~

~ lq ~ 2 ~

WO = A-92 17165 describes compositions comprising a core, a layer of excipient comprising a soluble material in water and a water-insoluble material, and a enteric coating. The nucleus contains the active ingredient S in combination with a blowing agent.
EP-A-0 210 5 ~ 0 describes compositions comprising a inert core, a layer containing the active ingredient, a layer of a swelling material and an enteric coating, or an inert core, a layer containing the active ingredient with a swelling material and an enteric coating.
These ~ e ~ x above documents do not allow a selective release of the active ingredient in an organ target, and moreover pose contamination problems of the active ingredient by the blowing agent.
_ 3 ~ MODIFIED SHEET

W096l04893 21 ~ 7 2 3 ~ / r. A / 7 ~

(c) a layer (3) containing at least one principle activated and (d) a layer (4) of a material that becomes permeable to water in a predetermined aqueous medium, this layer being 5 susceptible to rupture under the effect of the expansion of the core (1).
This composition makes it possible to obtain a composition pharmaceutical, in particular intended for administration orally, allowing selective release of a 10 active ingredient at a target organ. - ~
In the presence of the appropriate aqueous surrounding medium, the f layer material (4) is or becomes permeable ~ water;
water enters the composition and reaches the nucleus (1). The core (1) inflates at a speed controlled by the 15 elastic material (2), thus exerting a certain pressure on the outer layers. After a while, this pressure leads to the rupture of the layer (4) and to the setting in contact of the active ingredient layer (3) with the medium surrounding, which results in the immediate release of the 20 all of the active ingredient. Thanks to the layer (2) which leaves pass water but which is substantially insoluble in water, the active ingredient cannot migrate into the nucleus. We avoid thus the in situ formation of a dosage form to extended release or delay; the drawbacks of art 25 prior are therefore avoided.
according to one embodiment, in the present -:
composition, the core (1) has an expansion in volume, from 50 to 700 ~, preferably 100 to 500%, plu5 preferably from 150 to 300%.
According to another embodiment, in the present composition, relative proportions, by weight relative the total weight of the composition, of the different elements components (1) to (4) are as follows:
30 to 90%, preferably 50 to 70%, more preferably about 60 ~ by weight of (1);
1 to 6 ~, preferably 2 to 4%, more preferably about 3% by weight of (2);
1 to 60%, preferably 10 to 50%, more preferably about 30% by weight of (3);

~ W096 / 04893 ~ 1 ~ 7 ~ 3 4 P ~ llrh ~ ~ 1079 3 to 15%, preferably 5 to 9%, more preferably about 7 ~ by weight of ~ 4).
According to one embodiment, in the present composition, said layer material (4) being or becoming permeable to water in an aqueous medium predetermined is a water-soluble polymeric material in this predetermined medium, whose solubility depends on the pH, said material exhibiting solubility from a pH value between pH = 6.0 and pH = 8.0.
According to a variant of this embodiment, said layer (4) polymer material includes material polymer having a solubility from a value of pH 6.8.
According to one embodiment, in the present composition, the material of the layer (4) is a material gastro-resistant and entero-soluble.
According to one embodiment, in the present composition, the active substance is prednisolone or a of its pharmaceutically acceptable derivatives.
According to one embodiment, in the present composition, the layer (3) comprises 1 to 500 mg of principle active and preferably from 5 to 100 mg of active principle.
The subject of the invention is also said composition for its use as a medicine.
According to one embodiment, the use is a use as a medicament for the treatment of colon diseases.
The subject of the invention is also a method of preparation of a composition according to the invention, comprising the following steps:
(i) compression of the core (1) from a mixture powdery;
(ii ~ coating on said core (1) of the layer (2);
(iii) coating on said layer (2) of the layer (3) comprising at least one active ingredient; and (iv) coating on said layer (3) of the layer (4).
Any process known in the art suitable for the steps compression, coating, and capsule preparation, tablets, etc. can be used. The ingredients of 2 ~
W096 / 04893 PCT ~ R9 ~ 01079 -layers are provided in a conventional manner, for example under pulverulent form, in dissolved form in a solvent appropriate, etc. -The composition according to the invention is presented in a classic form, for example capsule, capsule, tablet, etc. This composition is particularly suitable for oral administration The dose of active ingredient to be administered can be formulated either under the single tablet, capsule or capsule form either under the form of mini dosage units which can be administered in once or more, depending on the active ingredient. These mini-forms are advantageous for the implementation of the invention.
The invention is now described in more detail in 1 ~ the following, and with reference to Figures l and 2.
Figure l shows a sectional view of a composition according to the invention;
Figure 2 represents a graph giving the profile of release for a composition according to the invention.
With reference to figure l, the core and the layers are indicated respectively ~ l) to (4).
The core (l) comprises a material which swells in presence of water, but which is insoluble in water and preferably is a neutral polymeric material.
2 ~ Any known bio-compatible polymer material and / or biodegradable conventionally used can be incorporated into the composition according to the present invention. We can cite to title of example: methylcelluloses of different weights molecular, polyvinyl alcohols, acrylic polymers, hydroxypropylmethylcelluloses, and generally everything natural or synthetic polymer as well as the copolymers derivative and the derivative mixtures capable of swelling at contact with water or an aqueous fluid.
The nucleus may optionally include any excipient conventionally used in art.
The layer ~ 2) deposited on the core constitutes a barrier which prevents the migration of the active ingredient in the nucleus and which controls the rate of nucleus expansion. This layer consists of a material, preferably polymer, 21 9 ~ 3 ~.
~ W096l04893 Y ~ llr ~ / Y

which allows the water present in the environment to be pagged until core, which is elastic and substantially insoluble in water. This material can for example be porous. All materials, polymers, copolymers and blends in drifting, having the above characteristics can be used. The polymer (2) has a elasticity defined as follows: ability to double at least volume, in contact with water at 37 ~ C, without film rupture Examples of compounds are: ethylcellulose plus hydroxypropyl methylcellulose, methylcellulose plus hydroxypropylmethylcellulose, Eudragit ~ NE30D, etc.
It has also been demonstrated that a composition comprising at least one hydrophilic polymeric material and one agent plasticizer led to a layer having a significant elasticity.
The layer (3) comprises at least one active principle, only or mixed with conventionally used exciPients in the pharmaceutical field or any other field in depending on the end use of the active ingredient. The active ingredient can be a biocide, an acaricide, a insecticide, bactericide, fungicide, drug, etc., and preferably a compound exhibiting activity pharmaceutical. Any compound with activity, soluble or insoluble in water, can be used.
The layer (3) can also consist of sub-layers, for example containing different active ingredients, possibly separated by sub-layers in suitable materials.
In what follows, and for the sake of convenience and simplicity, reference will be made to a composition pharmaceutical obtained from a principle pharmacologically active.
The layer ~ 4) is made of a material becoming permeable to water, and liable to rupture under the effect of nucleus expansion. The term ~ material becoming permeable to water in a predetermined aqueous medium ~
means that the material lets water through or is likely to let water pass after exposure to it given medium. The term ~ aqueous medium ~ is used here according to W096 / 04893 21 ~ PCT ~ R95 / 01079 -the classic acceptance of the term. For example, this material may become porous under the effect of its solubility in said environment or its degradation under the conditions prevailing in said medium. This material may break under the effect of the expansion of the core (1), once the water, after having crossed the layers ~ 4), ~ 3) and (2), caused the core to swell ~
This layer (4) can be made of a material, preferably polymer, likely to be degraded or dissolved by an element present specifically immediately upstream from or at the do ~ born site where the lib ~ ration must have location. For example, this material may correspond to a polymer enter ~ that degrades or dissolves under the effect of a given pH, or may correspond to a polymer which is specifically degraded by a given enzyme, by example a pancreatic or intestinal enzyme such as a esterase.
Any coating, preferably enteric, conventionally used in the pharmaceutical field can be used within the scope of the invention Examples of compounds are: acrylic polymers such as Eudragit ~ en combination with a plasticizing agent, such as dibutylphthalate or triethyl citrate, etc.
The core (1 ~ and the co-uches (2) to (4) may contain possibly ~ suitable additives known in the art, such as for example stabilizer, antioxidant, dye, plasticizer, lubricant, preservative, flavor, agents compression, etc. By the way, additional layers may be provided, such as an outer layer imparting an aroma and / or color and / or enhancing the acceptability of the drug and Jou allowing a marking.
As noted above, the mechanism is the following: in the presence of the appropriate aqueous surrounding medium, the material of the layer (4) allows water to pass through. The core (1) in the presence of water inflates at a speed controlled by the polymer coating (2), exerting some pressure on the outer layers. After some time, this pressure leads to the rupture of the layer (4) and to the contact of the active ingredient layer r3) with the medium 7 ~ q7 ~ 3 7 ~

surrounding, which results in the immediate release of L ~
all of the active ingredient. Thanks to the layer (2 ~ which leaves pass water ~ but which is substantially insoluble in water, the active ingredient cannot migrate into the nucleus.
1a present composition allows, by a double control, namely a control of the ~ p ~ n ~ i ~ n of the nucleus ~ 1) carried out by the elastic layer (2) and a control ~ of the place of degradation of the layer (4), to obtain a release selective and immediate active ingredient (3) at a given site, such as for example and preferably an organ target when the composition is preferably a pharmaceutical composition.
The composition of layers (1), (2) and (4) will be modified according to the speed of expansion of the core (1) which is required. We can note in particular that the more materials, preferably polymers, (2) and (4) are hydrophilic, the faster the penetration of water important and more the swelling speed of the nucleus is big. Furthermore, the speed of release of the principle active can be controlled by the nature of the constituent of the nucleus which offers a more or less strong expansion.
If, for example, we want the composition pharmaceutical releases the active ingredient in the colon, then, the layer (4) can consist of a coating enteric (i.e. gastro-resistant and entero-solubial including solubility depends on pH. In such a case, when the pharmaceutical system is going to be in the presence of a medium surrounding whose p ~ is greater than or equal to the value at from which the material (polymer) (4) dissolves, the layer (4) will begin to dissolve, which leads to the pore formation allowing the penetration of the fluid gastrointestinal in the composition. The gastro-fluid intestinal will cause core swelling, speed expansion of the nucleus should then be controlled so that the rupture of the coating (4) only appears at the level of the colon.
The following examples illustrate the invention without however limit its scope.

g F ~ ULLLE MODIFIED

Wog6 / o ~ s3 ~ 1 9 7 ~ 3 ~. ~ llrl Q ~ 1079 -~ x the 1:
By conventional methods, a tablet is prepared having the following characteristics:
- composition of the nucleus (1):
5 hydroxypropyl methylcellulose 26.00 mg microcrystalline cellulose 52.00 mg hydroxypropylcellulose 35.00 mg (low degree of substitution, L-HPC ~) colloidal silica 1.50 mg 10 st ~ magnesium arate 0.50 mg - composition of the layer (2):
ethyl cellulose 3.00 mg hydroxypropyl methylc = ellulose 2.50 mg dibutyl phthalate 1.50 mg lS - composition of the layer (3):
metasul ~ prednisolone obenzoate 31.43 mg hydroxypropyl methylcellulose ~ 20.00 mg - composition of the layer (4):
Eudragit ~ S100 14.00 mg 20 dibutyl phthalate 3.50 mg Fx on 2:. ~~
By conventional methods, a tablet is prepared having the following characteristics:
- composition of the nucleus (1):
25 hydroxypropyl methylcellulose: 26.00 mg microcrystalline cellulose 52.00 mg hydroxypropylcellulose 35.00 mg (low degree of substitution, L- ~ PC ~) colloidal silica 1.50 mg 30 magnesium stearate 0.50 mg - composition of the layer (2):
ethyl cellulose 3.00 mg hydroxypropyl methylcellulose 2.50 mg triethyl citrate 1.50 mg 35 - composition of the layer (3 ~:
metasul ~ prednisolone obenzoate 31.43 mg hydroxypropyl methylcellulose 20.00 mg ~ 0 ~ 1,972 ~
W096 / 04893 r_llr -_. L / Y

- composition of the layer (4):
Eudragit ~ slOO lo, Oo mg hydroxypropyl methylcellulose 4.00 mg triethyl citrate 3.50 mg5 E ~ e 3:
By conventional methods, a tablet is prepared having the following characteristics:
- composition of the nucleus tl):
hydroxypropyl methylcellulose 26.00 mg 10 microcrystalline cellulose 52.00 mg hydroxypropylcellulose 35.00 mg (low degree of substitution, L-HPC ~) colloidal silica 1.50 mg magnesium stearate 0.50 mg 15 - composition of layer t2):
Eudragit ~ ME30D 5.00 mg - composition of layer t3):
prednisolone metasulfobenzoate 31.43 mg hydroxypropyl methylcellulose 20.00 mg 20 - composition of layer t4):
Eudragit ~ S100 10.00 mg hydroxypropyl methylcellulose 4.00 mg triethyl citrate 3.50 mg ~ x ~ the 4:
By conventional methods, a tablet is prepared having the following characteristics:
- composition of the nucleus (1):
hydroxypropyl methylcellulose 26.00 mg microcrystalline cellulose 52.00 mg 30 hydroxypropylcellulose 35.00 mg (low degree of substitution, L-HPC ~) colloidal silica 1.50 mg magnesium stearate 0.50 mg - composition of the layer (2):
Eudragit ~ NE30D 5.00 mg - composition of the layer (3):
prednisolone metasulfobenzoate 31.43 mg hydroxypropyl methylcellulose 20.00 mg 21 97 ~
W096 / 04893 r ~ llrl __ [l ~ lY -- composition of the layer (4):
hydroxypropyl methylcellulose 15.0Q mg dibutyl phthalate 3.00 mg E ~~ - ~, the 5th:
Six in vivo clinical study healthy volunteers (3 men, 3 women). We are preparing placebo tablets containing 2 mg of enriched samarium oxide in isotope Sm 153, from the composition of example 1, in which the ac ~ if principle has been replaced by a cellulose derivative. Such tablets are administered to patients. Using a classical technique scintigraphy, we determine the anatomical position and the tablet disintegration time.
After a light breakfast, each subject receives a tablet with 2 ~ 0 ml of water. The results are saved periodically. Then each subject receives a slight lunch and recording is continued. The results are given in FIG. 2. This figure, which indicates the time of arrival in the colon and the time of initial disintegration of the tablet, clearly shows that the radiolabelled placebo disintegrates through the colon which means that an active ingredient would be released selectively e ~ immediately also in the colon.

Claims (11)

1. Composition comprising, successively:
(a) a core (1) consisting of a swelling material in the water;
(b) a layer (2) of an elastic material, leaving pass water and insoluble in water;
(c) a layer (3) containing at least one principle asset; and (d) a layer (4) of a material becoming permeable to water in a predetermined aqueous medium, this layer being likely to rupture under the effect of the expansion of the kernel (1). 2. Composition according to claim 1, in which the core (1) presents an expansion in volume, from 50 to 700%, preferably 100 to 500%, more preferably 150 to 300% 3. Composition according to claim 1 or 2, in which the relative proportions, by weight in relation to the weight total of the composition, of the different elements components (1) to (4) are as follows:
to 90%, preferably 50 to 70%, plus preferably about 60% by weight of (1);
1 to 6%, preferably 2 to 4%, more preferably about 3% by weight of (2);
1 to 60%, preferably 10 to 50%, more preferably about 30% by weight of (3);
3 to 15%, preferably 5 to 9%, plus preferably about 7% by weight of (4). 4. Composition according to any one of claims 1 to 3, wherein said material of the layer (4) becoming permeable to water in a predetermined aqueous medium is a water-soluble polymeric material, the solubility of which depends on the pH, said material exhibiting a solubility at from a pH value between pH = 6.0 and pH=8.0. 5. Composition according to claim 4, in which said polymeric material of the layer (4) comprises a material polymer having a solubility from a value of pH of 6.8. 6. Composition according to any one of claims 1 to 5, in which the material of the layer (4) is a gastro-resistant and enteric-soluble material. 7. Composition according to any one of claims 1 to 6, wherein the active ingredient is prednisolone or one of its pharmaceutically acceptable derivatives. 8. Composition according to any one of claims 1 to 7, wherein layer (3) comprises 1 to 500 mg of active principle and preferably from 5 to 100 mg of principle asset. 9. Composition according to any one of claims 1 to 8, for its use as a medicine. 10. Composition according to claim 9, for its use as a medicament for the treatment of colon diseases. 11. Process for preparing a composition according to one any of claims 1 to 8, comprising the steps following:
(i) compression of the core (1) from a mixture powdery;
(ii) coating on said core (1) of the layer (2);
(iii) coating on said layer (2) of the layer (3) comprising at least one active principle; and (iv) coating on said layer (3) of the layer (4).